Neurological disorders comprise several major diseases as described in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV-R) [3]. It is well-established that a particular neurological disorder may involve complex interactions of multiple neuroreceptors and neurotransmitters, and, conversely, a single neuroreceptor may be implicated in several disorders, both neurological and non-neurological. For example, the serotonin receptor is implicated in numerous disorders such as depression, anxiety, pain (both acute and chronic), etc.; the dopamine receptor is implicated in movement disorder, addiction, autism, etc; and the sigma receptors are involved in pain (both acute and chronic), and cancer. Many of the receptors that are found in the brain are also found in other areas of the body, including gastrointestinal (GI) tract, blood vessels, and muscles, and elicit physiological response upon activation by the ligands.
The rational drug design process is based on the well-established fundamental principle that receptors, antibodies, and enzymes are multispecific, i.e., topologically similar molecules will have similar binding affinity to these biomolecules, and, therefore, are expected to elicit similar physiological response as those of native ligands, antigens, or substrates respectively. Although this principle, as well as molecular modeling and quantitative structure activity relationship studies (QSAR), is quite useful for designing molecular scaffolds that target receptors in a “broad sense,” they do not provide sufficient guidance for targeting specific receptor subtypes, wherein subtle changes in molecular topology could have substantial impact on receptor binding profile. Moreover, this principle is inadequate for predicting in vivo properties of any compound; hence, each class of compound needs to be evaluated in its own right for receptor subtype affinity and selectivity, and in in vivo animal models to establish efficacy and toxicity profiles. Thus, there is a sustained need for the discovery and development of new drugs that target neuroreceptor subtypes with high affinity and selectivity in order to improve efficacy and/or minimize undesirable side effects.
Serotonin and sigma receptors are widely distributed throughout the body. To date, fourteen serotonin and two sigma receptor subtypes have been isolated, cloned, and expressed. Serotonin receptors mediate both excitatory and inhibitory neurotransmission, and also modulate the release of many neurotransmitters including dopamine, epinephrine, nor-epinephrine, GABA, glutamate and acetylcholine as well as many hormones such as oxytocin, vasopressin, corticotrophin, and substance P [4, 5]. During the past two decades, serotonin receptor subtype selective compounds have been a rich source of several FDA-approved CNS drugs. Most of these serotonin receptor subtypes have been focus of research in the past couple of decades and this effort has led to the discovery of important therapeutics like Sumatriptan (5-HT1B/1D agonist) for the treatment of migraine, Ondansetron (5-HT3 agonist) for the treatment of radiation or chemotherapy-induced nausea and vomiting, and Zyprexa (5-HT2A/D2 antagonist) for the treatment of schizophrenia. Therapeutic targets have been identified for 5-HT4 (learning and memory) [6], 5-HT5A (cognition, sleep) [7], 5-HT6 (learning, memory) [8] and 5-HT7 (pain and depression) [9, 10], and some selective ligands have been prepared for all of these receptors with the exception of 5-HT5A. In contrast, the sigma receptors have not received as much attention as the serotonin subtypes. Only recently has there been a substantial interest in sigma receptors, particularly due to its importance in pain and cancer. In particular, σ1 receptor is implicated in pain, and σ1 antagonists have been shown to have antinociceptive properties [11]. On the other hand, σ2 receptor is overexpressed in highly proliferating cells such as cancer cells, and activation of this receptor induces apoptosis. Hence, σ2 agonists may have potential use as anticancer agents [12].
Numerous receptors are involved in the pain process, and currently, there is clear evidence that both 5-HT7 and σ1 receptors directly involved in pain pathway, and selective ligand that target these receptor subtypes have been prepared and tested. For example, AS-19 (1), a selective 5-HT7 agonist and BD-1063 (2), a σ1 antagonist, have been shown to be
effective in inhibiting pain [9, 11]. However, there is no FDA approved medication based on 5-HT7 or sigma receptors, albeit many agents are in preclinical and clinical development stages. Thus, new medication for the treatment of chronic pain is in great need, particularly due to increasing aging and diabetic populations.
Rajagopalan[13, 14] and Adams et al. [15] disclosed the pentacyclic scaffolds incorporating the γ-carboline pharmacophore 3-6, where the two phenyl rings are fused at the ‘b’ and ‘f’ positions in the 7-membered D-ring. In particular, the sulfur analog 6b has been shown recently to have atypical antipsychotic properties [16]. However, other pentacyclic analogs, where the E-phenyl ring being fused at other positions in the 7-memebered D-ring, have not been disclosed.
